DESCRIPTION: (Applicant's Description) The long-term objectives of my research is to develop and apply combinatorial chemistry for basic research and drug development. Combinatorial chemistry has become one of the most important technologies in recent years for both drug discovery and basic research. Millions of compounds can be generated and screened for their ability to bind to a specific target macromolecule or to elicit a specific biological response. About the same time, several molecular biology based tools have been developed to rapidly analyze changes in gene expression. Differential display, serial analysis of gene expression or SAGE and more recently, cDNA microarray technology are some of the very powerful technology that enables one to identify the unique genes expressed in a disease-state. Although 2-dimensional polyacrylamide gel electrophoresis was first described in 1975, it was not until recently that this technique resurfaces as a potential method for the identification of altered protein expressed in disease-tissues. In this proposal, we hypothesize that by applying the "one-bead one-compound" combinatorial library method to the concept of differential genomic or protein display, we may be able to rapidly identify ligands for altered phenotype (proteins) in disease-tissues. In principle, this new approach will enable us to screen millions of ligands against thousands of proteins simultaneously in "one-pot" and only the altered proteins that bind to specific ligands from the library will be identified. The main objective of this research is to develop this novel technology using 3T3 cells and v-src transfected 3T3 cell lines as our model system.